In 2012 over 15 million people in the United States were diagnosed with coronary heart disease and it is currently the leading cause of death. Coronary arteries are small diameter blood vessels (SDBV), on average 4 mm in diameter, and once occluded, they pose a serious risk for myocardial infarction. A stent is typically deployed to open-up the narrowed vessel; however, restenosis may occur, necessitating replacement of the vessel. Whereas large diameter blood vessels are readily substituted with Teflon or other synthetic-based constructs, they fall short of meeting the physiological requirements for SDBV, and are only replaced with an autologous graft. Large diameter vessels benefit from high blood flow velocities, which reduce blood-graft interface contact activation, and thereby minimize the potential for thrombus formation. The opposite is true with SDBV; low blood flow velocities increase interface time and the propensity for thrombus formation, which occludes the lumen of vessel grafts. The current standard of care for SDBV bypass surgeries are the internal mammary artery, saphenous vein, radial artery and the right gastroepiploic artery. Nevertheless, this alternative increases the risk of comorbidity and the patients can go through several rounds of surgical procedures. These autografts, although mechanically inferior, provide a blood-compatible vessel solution. However, limited availability and donor site comorbidity are major points of concern for employing an autograft for SDBV. On the other hand, differences in diameter and compliance to the natural vessels in the anastomosis area might lead to intimal hyperplasia and failure of the graft.
Tissue engineered SDBV are poised to replace autografts by recapitulating the native structure and function of blood vessels without requiring tissue to be harvested. Structurally, blood vessels are composed of three distinct layers: the tunica externa (adventitia), tunica media, and tunica intima. The tunica externa primarily provides a protective coating to the vessel, which doubles as an attachment point to tissues. The tunica media consists mainly of smooth muscle cells and elastic tissue, oriented circumferentially around the vessel, providing compliance and resilience to arterial pressure. Finally, the endothelial lining of the tunica intima provides the blood-compatible, luminal interface. Tissue engineering approaches to construct SDBVs have focused their research on recreating the media and the intima layers, because a non-thrombus forming surface and a mechanical behavior and durability are desirable characteristics in engineered grafts.
Many attempts for engineering SDBV consisted of variable scaffold compositions and fabrication techniques intended to replicate vessels' natural layers. Decellularized scaffolds employ the natural structure of allografts to provide the proper extracellular environment for subsequent cell seeding and repopulation. Electrospinning is a novel technique that has been widely reported due to the fibrous, durable matrix it can produce, which can be deposited in an aligned manner, wrapped around the vessel for recreating the mechanical strength that the tunica media has or as a scaffold for cell seeding. A third approach consists in dipping a thin rod into a hydrogel solution, which upon gelation provides a tubular structure. This is a very promising method as it allows an easy layer-by-layer fabrication, recapitulating the unique structure and function of each vascular layer. However, it has neither been explored to generate more complex multilayer vessel-like structures nor used to fabricate cell-laden concentric layers.
Scalability and reproducibility of results is a major concern in the biomedical field, where reports indicate that up to 90% of studies couldn't be reproduced. A reason for the lack of reproducibility is the artist-like, nuanced method by which many studies are performed, especially those of tissue engineering, where each implant is a one-off device. A means for overcoming the just-right methodology is to automate processes using simple robotics, removing the human element and standardizing the process. Never before has this prospect been as available as it is now, with simple, inexpensive microprocessors widely available, such as the Arduino platform. This open-source microprocessor is easy to program and supports a number of “shields” which add functionality to the system, such as a stepper motor driver. By automatizing the fabrication of tissue engineered SDBV it is possible to dramatically increase the production volume and decrease sample-to-sample variability, which can confound results and reduce the project's success and medical translation.